The immune system is comprised of a complex network of autonomous cells working together to manage a chaotic situation. The regulation of the immune network is equally complex, characterized by hubs of activation control. The dendritic cell (DC) represents one hub of immune control via its unique abilities to regulate activation of CD4+ T cells. In turn, CD4+ T cells are able to affect the activity of a wide variety of immune cells of both the adaptive and innate categories. During an initial interaction, DCs present antigen (Ag) in the context of MHC class II molecules for recognition by CD4+ T cells via their T cell receptor (TCR). Binding of Ag by the TCR represents signal one, but further stimulation derived from costimulatory signals is required for full activation of T cells via DCs. Many co-stimulatory receptor-ligand pairs have been identified between T cells and DCs. The prototypical costimulation interacting pairs on T cells and DCs are CD154-CD40 and CD28-B7 (T-DC respectively). Since their identification, experimental manipulation of these receptors and ligands has proven to be a powerful tool in modulating a wide variety of immune responses ranging from transplant tolerance and autoimmunity to tumor rejection (1-7).
The present invention overcomes previous shortcomings in the art by demonstrating that PlexA1 expressed on DCs and Sema6D expressed on T cells (e.g., CD4+ T cells) and on B cells, represent a novel receptor-ligand costimulation pair, capable of regulating immune system activity.